BETA(1) INTEGRINS PARTICIPATE IN THE HYPERTROPHIC RESPONSE OF RAT VENTRICULAR MYOCYTES

Multiple signaling pathways have been implicated in the hypertrophic r esponse of ventricular myocytes, yet the importance of cell-matrix int eractions has not been extensively examined. Integrins are cell-surfac e molecules that Link the extracellular matrix to the cellular cytoske leton. They can function as cell signaling molecules and transducers o f mechanical information in noncardiac cells. Given these properties a nd their abundance in cardiac cells, we evaluated the hypothesis that beta(1) integrin function is involved in the alpha(1)-adrenergic media ted hypertrophic response of neonatal rat ventricular myocytes. The hy pertrophic response of this model required interaction with extracellu lar matrix proteins. Specificity of these results was confirmed by dem onstrating that ventricular myocytes plated onto an anti-Pi integrin a ntibody supported the hypertrophic gene response. Adenovirus-mediated overexpression of beta(1) integrin augmented the myocyte hypertrophic response when assessed by protein synthesis and atrial natriuretic fac tor production, a marker gene of hypertrophic induction. DNA synthesis was not altered by integrin overexpression. Transfection of cultured cardiac myocytes with either the ubiquitously expressed beta(1A) integ rin or the cardiac/skeletal muscle-specific beta(1) isoform (beta(1D)) activated reporter expression from both the aerial natriuretic factor and myosin light chain-2 ventricular promoters, genetic markers of ve ntricular cell hypertrophy. Finally, suppression of integrin signaling by overexpression of free beta(1) integrin cytoplasmic domains inhibi ted the adrenergically mediated atrial natriuretic factor response. Th ese findings show that integrin ligation and signaling are involved in the cardiac hypertrophic response pathway.